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. 2020 Apr 24;10(5):211. doi: 10.1007/s13205-020-02207-3

A review on myricetin as a potential therapeutic candidate for cancer prevention

Nazia Afroze 1, Sreepoorna Pramodh 2, Arif Hussain 1,✉, Madiha Waleed 1, Kajal Vakharia 1
PMCID: PMC7181463  PMID: 32351869

Abstract

Myricetin, one of the most extensively studied polyphenols, is present abundantly in various fruits and vegetables and exhibits diverse pharmacological properties. The multifaceted biological action of myricetin against tumor heterogeneity makes it an impressive anticancer agent whose efficacy has been confirmed by an overwhelming number of studies. Myricetin shows its therapeutic potential by targeting and modulating the expression of various molecular target which are involved in inflammation, cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. Myricetin deters tumor progression by inducing apoptosis via both intrinsic and extrinsic pathway, activating/inactivating several signaling pathways, and reactivating various tumor suppressor genes. This comprehensive review represents the effect of myricetin on various hallmarks of cancer with insight into the molecular mechanism employed by myricetin to mitigate cell proliferation, angiogenesis, metastasis, and induce apoptosis. In addition, enhanced bioavailability of myricetin through conjugation and its increased efficacy as an anticancer agent when used in combination are also highlighted.

Keywords: Myricetin, Apoptotic proteins, Caspases, ROS, TNF, NLRP3 inflammasome, Immunomodulation

Introduction

Cancer is a pleiotropic disease caused by the uncontrolled proliferation of cells and is the second leading cause of death after cardiovascular diseases worldwide. According to the latest GLOBOCAN 2018 database, the number of cancer-related deaths will be 9.6 million in 2018 and it is continuously rising (Bray et al. 2018). One out of every 8 men and 11 women die because of cancer globally, of which lung cancer and breast cancer are predominant in men and women, respectively (source: WHO, February 2017). Cancer is a multistep, multi-genetic, multifactorial disorder including chromosomal abnormalities. Apart from genetic alterations, epigenetic changes like DNA methylation and histone modification also play a vital role in the development of cancer. Various conventional therapies for treating cancer includes surgery, radiation therapy, hormone therapy, immune therapy, etc. However, these treatments have enormous side effects due to their lack of specificity. They may attack healthy cells that are not the direct target of chemotherapy or irradiation. Therefore, in the past two decades, phytochemicals have been considered for cancer treatment as they are natural, non-toxic, pharmacological agents, and show differential response against cancer cells (Amararathna et al. 2016; Di Muzio et al. 2017). The various classes of polyphenols which exhibit potent anti-cancer property are catechins, flavonols, flavones, flavonols, isoflavones, anthocyanidins, etc. However, the current comprehensive review focusses on myricetin, a flavonol. Myricetin is a molecule with diverse pharmacological properties which also include antioxidant, anti-inflammatory, anti-cancer activity, and epigenetic modulation.

The objective of this review is to consolidate and offer a mechanism through which myricetin modulates the expression of various molecular targets. Myricetin targets multiple hallmarks of cancer such as cell cycle, cell proliferation, apoptosis, inflammation, anti-oxidation, angiogenesis, immunomodulation, metastasis, invasion, etc. by deterring tumor progression and mediating apoptosis as observed in various human cancer cell line and mouse model.

Sources, chemistry, and bioavailability of myricetin

The flavonol, myricetin (3, 5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-4-chromenone), is a phenolic compound which is found profusely in different plant-based dietary agents like tea, berries, vegetable, grapes, wine, walnut, etc. It was initially extracted from Myrica nagi by Perkin and Hummel in 1896 as a light yellow colored crystal. Myricetin is often referred to as hydroxy quercetin because of the presence of an additional -OH group and exists in two forms: free form and glycosidically-bound form. Myricetin is structurally composed of a 15- carbon skeleton with two aromatic rings (A and B), which remains joined via a three carbon chain which cyclizes and adds the third ring (C) to the structure (Semwal et al. 2016) (Fig. 1). Despite the polar nature of myricetin, it is sparingly soluble in water, and therefore, its bioavailability is very low. Although it dissolves readily in DMSO, acetone, tetrahydrofuran, etc., the compound is thermolabile and is most stable at pH 2. The recently proposed idea to enhance the bioavailability of the compound is by employing microemulsions55 and nanosuspensions56 for oral administration (Devi et al. 2015).

Fig. 1.

Fig. 1

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Chemical structure of Quercetin and Myricetin

Myricetin displays a variety of important biological and pharmacological activities. Biologically, it acts as nutraceuticals and exhibits antioxidant properties, while the pharmacological activities include anti-inflammatory, analgesic, antitumor, hepatoprotective, and antidiabetic effects.

Myricetin affects various hallmarks of cancer

The potent anti-cancer activity of myricetin has been established by extensive research and it has been substantiated that the compound shows cytotoxicity towards various human cancer cell line, both in vitro and in vivo. It targets almost all the hallmarks of cancer by acting as an antioxidant, anti-inflammatory agent, apoptosis inducer, inhibitor of cell proliferation and growth, immunomodulator, anti-metastatic agent, and inhibitor of angiogenesis (Fig. 2). It encumbers cancer development and progression by modulating the expression of numerous molecular markers that are involved in cancer progression. Here we will discuss the effect of myricetin on signal transduction and cancer markers as described.

Fig. 2.

Fig. 2

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Myricetin affects cancer cells by modulating the expression of various molecular targets that regulate the activity of various hallmarks of cancer such as angiogenesis, cell proliferation, inflammation, cell cycle, apoptosis, metastasis, and immunomodulation

Effects of myricetin as an anti-oxidative agent

Oxidation is a chemical reaction that leads to the generation of free radicals by involving different chain reactions. Elevated level of free radicals or reactive oxygen species (ROS) in cells is one of the hallmarks of cancer and it has been found that the levels of ROS is significantly higher in tumor cells. Several in vitro studies have been conducted to evaluate the antioxidant effect of myricetin. One such study used a fluorescent probe to detect the ROS level in MCF-7 breast cancer cell line by assessing the cellular fluorescence intensity, using the DCF assay. CHP is an oxidizing agent that converts dihydrofluorescein diacetate (DCFH2) to fluorescent dichlorofluorescein (DCF), thus increasing the fluorescent intensity in untreated control cells. In treated cells, myricetin reduces the level of DCF by inhibiting CHP and therefore, there is a decline in fluorescent intensity. This shows that myricetin can cross the cell membrane and act as a strong radical scavenging agent in the polar intracellular environment (Barzegar 2016). Xanthine dehydrogenase (XDH) can be oxidized readily and converted to XOD (xanthine oxidase) which is widely present in most organisms, right from bacteria to mammals. Unlike XDH, XOD reacts solely with dioxygen and generates O2− (superoxide anion) and H2O2 (hydrogen peroxide). Studies have reported that accumulation and generation of free radicals are associated with multiple ailments like inflammation, ischemia, and hypertension. XOD inhibitors from dietary agents can be promising to combat these diseases. Various dietary agents, like chrysin, fisetin, quercetin, etc., were reported to have a strong inhibitory effect against XOD, therefore they prevent generation of O2−. Zhang et al. have reported that myricetin also inhibits the activity of XOD in a dose-dependent manner and its activity reduces to 50% at a concentration of (8.66 ± 0.03) × 10–6 mol L1. Additionally, myricetin’s superoxide scavenging activity was found to be nearly 56% at a concentration of 6.0 × 10–5 mol L−1. Hence, it was concluded that myricetin has the potential to inhibit the synthesis of superoxide anion by xanthine oxidase, thereby proving to be a potent antioxidant (Zhang et al. 2017).

Effects of Myricetin as an anti-inflammatory agent

As inflammation is one of the hallmarks of cancer, therefore, a potent anti-cancer agent should be able to reduce the level or prevent inflammation. Myricetin demonstrates great inhibitory efficiency towards inflammation markers. Multiple researches have been conducted to investigate the anti-inflammatory properties of myricetin. One such study focused on the effect of myricetin on HepG2 cells. Myricetin treatment was responsible for reducing the level of inflammatory markers such as iNOS and COX−2 in a dose-dependent manner over the untreated control. Besides, myricetin also inhibited the activity of various cytokines such as IL-2 and IL-6, TNF α, IFN-γ, etc., thereby demonstrating its strong anti-inflammatory nature (Li et al. 2019). NLRP3 inflammasome is a cytosolic complex that plays a dual role by acting on innate immune response as well as plays a significant role in multiple inflammatory diseases. Myricetin impedes the NLRP3 inflammasome assembly by increasing ROS independent ubiquitination of NLRP3 and decreasing ROS dependent ubiquitination of ASC (apoptosis-associated speck-like protein containing a CARD). This consequently prevents ASC oligomerization as NLRP3 and ASC interaction are interrupted (Chen et al. 2019).

In an inflammation-driven colorectal tumorigenesis model, myricetin is accountable for inhibiting tumor progression by reducing the levels of various inflammatory markers. In another study, where mice were treated with 40 mg/kg and 100 mg/kg myricetin, it is also responsible for decreasing the size of the tumor from 4.2 ± 0.45/colon to 3.2 ± 0.45/colon (P < 0.05) and 2.8 ± 0.45/colon (P < 0.01), respectively. The colonic polyp size also decreased significantly in myricetin treated mice (3.6 ± 0.54/colon and 3.2 ± 0.83/colon for 40 and 100 mg/kg, respectively) compared to control mice (5.2 ± 0.7/colon). Myricetin, in various ways, restores the normal histological features of cancerous cells by decreasing the severity of inflammatory lesions and tumorigenesis to mild form (Zhang et al. 2018).

Myricetin has been found to significantly decrease the levels of cyclin D1 and proliferating cell nuclear antigen (PCNA) involved in the growth of adenomatous polyps in colonic tumorigenesis. NF-κB is responsible for transforming inflamed colonic cell to tumor, and myricetin treatment inhibits colonic inflammation as well as colitis-driven tumorigenesis by inhibiting NF-κB and COX−2 signaling pathways. It was further confirmed that myricetin treatment in mice led to the reduced expression of NF-κB. Additionally, the phosphorylation of NF-κB (in colonic mucosa) is prevented by myricetin, whose immediate growth response gene is COX-2. It has been demonstrated that TNF-α induces Cyclin D1 and COX-2, which have a binding site for NF-κB at their promoter region. Moreover, myricetin treatment in mice downregulates the expression level of TNF-α while the COX-2 was also found to be reduced.

Increased level of inflammatory cytokines is the key to prognostic detection of colitis and colon cancer. It has been reported that level of IL-1β and IL-16 are higher in the control (untreated mice) than the treated mice which show the significant reduction of both IL-1β (65.6%, 40 mg/kg; 34%, 100 mg/kg) and IL-16 (32.3%, 40 mg/kg; 22.8%, 100 mg/kg) by myricetin treatment, respectively (P < 0.001). Simultaneously, the changes in the mRNA level were also in concordance with the protein expression. Additionally, it was established that myricetin treatment significantly reduced the levels of GM-CSF, M-CSF, TNF-α, and IL-6 by ELISA (Zhang et al. 2018).

NF-α is a crucial cytokine that is involved in inflammation and myricetin shows great inhibitory efficacy (approximately 70%) toward TNF-α when compared with 14 different flavanols. Myricetin was further analyzed to evaluate its effect on different tumor-related protein kinases through radiometric protein kinase assay. The results indicate that the lowest concentration of myricetin (3 μM) has a potential to decrease the activity of 9 kinases (AXL, BRAF, TRK-β, SRC, PLK4, KDR, and IGF1-R) up to 90% (Stoll et al. 2019).

Effect of myricetin on apoptosis

The number of cells in an organism is maintained by apoptosis, a homeostasis. However, disruption of this balance may lead to cancer. Evasion of apoptosis is an important hallmark of tumorigenesis. The apoptotic evasion of cancer cells is sustained by the upregulation of anti-apoptotic protein, downregulation of pro-apoptotic protein, reduced expression of caspases (caspase-3, caspase-8 and 9), and reduced expression or inactivation of tumor suppressor gene like p53, Rb. The modulation in expression of these pro-apoptotic, apoptotic inhibit, and anti-apoptotic proteins is regulated by various signal transduction pathways. In these pathways, interaction of ligands with their receptors is important to progress towards apoptosis, e.g. these interactions include FasL (CD95L) and TNFL binding with Fas (CD95) and TNF-α, respectively. In this context, myricetin is quite efficacious in inducing selective apoptotic cell death over normal cells in various types of cancers, both in vitro and in vivo. Among the gynecological cancers, ovarian cancer is associated with the highest mortality rate in females worldwide. Apoptosis induction by myricetin in various types of cancer such as A2780 and OVCAR3 ovarian cancer cells, A431 human skin cancer, and MCF-7 human breast cancer cells occurs by upregulating BAX expression and significant downregulation of Bcl-2 compared to untreated cells (Table 1). In A2780, OVCAR3, and MCF-7 cells, myricetin induces apoptosis through intrinsic pathway as the cleaved Caspase-3 expression was found to be increased compared to the untreated control (Zheng et al. 2017; Jiao and Zhang 2016; Sun et al. 2018). In A431 cells, myricetin enhances apoptotic damage of cancer cells via increased production of ROS and by reducing mitochondrial membrane potential.

Table 1.

The mechanism of apoptosis induction by Myricetin in different types of cancer in human

Cell lines Mechanism of apoptosis induction/IC50 References
Activity of cell line
 Esophageal cancer
  EC9706 The expression levels of Survivin, Cyclin D1, and Bcl-2 were downregulated to induce apoptosis which is further enhanced by upregulating the expression of caspase-3 and p53 Wang et al. (2014)
 Ovarian cancer
  A2780, OVCAR3 Cell viability is ~ 25 μM for 48 h. Induces apoptosis by upregulating pro-apoptotic regulating pro-apoptotic protein Bax and cleaved caspase-3 and downregulating anti-apoptotic protein Bcl-2. Myricetin increases the chemosensitivity of paclitaxel by increasing the cell viability Zheng et al. (2017)
 Human colon cancer
  HCT-15 IC50 ~ 55 μM in 24 h. Myricetin induces apoptosis by increasing expression of pro-apoptotic protein i.e. Bax, Bak and mitochondrial dysfunction through AIF whereas it downregulates the expression of anti-apoptotic protein Bcl-2 Ma et al. (2019)
 Hepatocellular carcinoma
  HepG2 Myricetin decreases the cell viability by upregulating the ratio of BAX /BCL2 ratio, Activation of casapse-3, 9 and cytochrome C release Kim et al. (2014)
 Breast cancer
  MCF-7 The cell viability was reduced with 80 µM of myricetin for 12 h and 24 h. It induces apoptosis by increasing Bax and caspase activation. Cell viability were suppressed via PAK1/ MEK/ ERK signaling pathway Jiao and Zhang (2016)
  Human BCBM,4T1 20–40 µM myricetin reduced the cell viability of MDA‐Mb‐231Br cells in 48 h Lee et al. (2012)
 Prostrate cancer
  PC3, DU145 Shows cytotoxicity at IC50 47.6uM and 55.3 uM, respectively. Induces apoptosis by upregulating both cleaved caspase-3 and caspase 9 and by inhibiting ERK1/2 and Akt phosphorylation Conley-LaComb et al. (2013) and Ye et al. (2018)
 Pancreatic cancer
  MIA PaCa-2 Induces apoptosis both in vitro and in vivo by releasing cyto-c and upregulating the and S2-013 expression of Cyt-3 and Cyt-9 Phillips et al. (2011)
 Thyroid cancer
  SUN-790 HPTC Induces apoptosis through mitochondrial disrupting mitochondrial function cells which results in release of AIF and activation of caspase (caspase 3, 8, 9 and PARP-1) change Bcl-2/Bax ratio and AIF release Kwun et al. (2017)
 Skin cancer
  A431 IC50 of 20 μM. Apoptotic induction is via change in the expression of Bcl2/Bax ratio, apoptotic damage of cancer cells via increased production of ROS and by reducing mitochondrial membrane potential Sun et al. (2018)
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Wang et al. have reported that in oesophageal cancer, EC9706 cells, myricetin and 5-FU treatment have downregulated the expression of Cyclin D1, Bcl-2 (anti-apoptotic protein), and survivin when used alone compared to the untreated control. Further, when 5-FU and myricetin were used in combination, the expression of Cyclin D1, Bcl-2 (anti-apoptotic protein) and survivin was further reduced. Caspase-3 and P53 were further increased than in myricetin or 5-FU group when used alone (P < 0.05) (Wang et al. 2014).

Similarly, in T24 bladder cancer cell also myricetin induces apoptosis by shifting the expression ratio of Bax /Bcl-2 and upregulating the cleaved caspase-3. Besides, myricetin accentuates apoptosis by downregulating Akt /PI3K responsible pathway for continuous proliferation which is upregulated in many cancers. Myricetin-treated cells show a significant reduction in phosphorylated AKT at ser 473 residue than untreated cells, which is a downstream target of PIK3. Therefore, myricetin leads to downregulation of PI3K and serine/threonine kinase (Sun et al. 2012).

In HCT-15 human colon cancer cells, myricetin induces apoptosis by the enhancement of AIF release from mitochondria which signals the increase of BAX/BCL2 ratio and BAK expression (Kim et al. 2014). Therefore, myricetin induces apoptosis in HCT-15 through AIF, BAX/BCL2 dependent, and caspase-independent pathway. In contrast to HCT-15 cells, myricetin reduces cell viability of HepG2 human colon carcinoma cells through a caspase-dependent pathway by changing the mitochondrial membrane potential which causes the release of cytochrome C from the mitochondria. Cytochrome-c, in turn, further triggers the activation of caspase-3 and PARP-1 (a substrate of caspase) (Ma et al. 2019). Further, myricetin decreases the expression of Bcl-2 and increases the expression of Bax and Bad, thereby induces cell death of HepG2 cells. Myricetin inhibits Akt-induced phosphorylation of p70S6K and Bad protein, which otherwise increases cell viability of cancer cells. Therefore, myricetin acts as a potent therapeutic agent against colon cancer, inducing apoptosis through cytochrome-c and Akt/p70S6K/Bad pathway (Kim et al. 2014).

Prostate cancer (PC) is a leading cause of cancer-related death in men and the conventional hormonal (androgen) deprivation treatment can control the progression of PC cells during the primary phase; however, patients develop metastatic castration-resistant prostate cancer. Myricetin has shown to reduce the cell viability of prostate cancer cell line PC 3 and DU 145 by upregulating both cleaved caspase-3 and caspase 9, compared to the control and by inhibiting phosphorylation of ERK1/2 and Akt (Ma et al. 2019; Yea and Zhanga 2018).

Ma et al. have reported that myricetin inhibits the action of Human Flap Endonuclease 1(hFEN1) in a dose-dependent manner in human intestinal epithelial HT-29 cells as it was thought that myricetin would be effectively absorbed by HT-29 cells. hFEN1 is a DNA repair enzyme that ensures genome stability and is found to be upregulated in many cancers. Moreover, hFEN1 negatively controls the phosphorylation γH2AX i.e., downregulation of hFEN1 expression causes the phosphorylation of γH2AX, which is a hallmark for DNA double-strand break which leads to apoptosis (Ma et al. 2019).

Pancreatic cancer is a disease with poor prognosis and obdurate to cancer conventional treatment modalities; therefore, the use of dietary chemopreventive agents may prove to be beneficial. Myricetin has been found to induce cell death in a dose-dependent manner on pancreatic cancer cells through mitochondrial-dependent pathways by releasing cyt-c and upregulating the expression of caspases (caspase-3 and caspase-9) compared to the untreated control (Phillips et al. 2011). In addition to mitochondrial-dependent apoptosis, myricetin also acts by inhibiting PI3-kinase pathway in pancreatic, lung, and cervical cancer and it does so, by inhibiting the phosphorylation of Akt, a marker of PI3-kinase pathway. Further, administration of myricetin in two orthotopic mouse model of pancreatic cancer (MIA PaCa-2 and S2-013) decreased tumor growth and development. In vivo studies have confirmed that the treatment of Xenograft with 5 mg/kg of myricetin exerted antitumor effects on bladder cancer (Sun et al. 2012).

Thyroid cancer is quite predominant among women and its number has been increasing in the past three decades. Myricetin exhibits cytotoxicity towards thyroid cancer HPTC cell line by disruption of mitochondrial function which results in the release of AIF and activation of caspase (caspase 3, 8, 9 and PARP-1) cascade. Simultaneously, it increases the expression of BAX while decreasing the expression of Bcl-2. Together, this finding revealed that myricetin induces cell death by mitochondrial dysfunction (Table 1).

Effects of myricetin on cell survival, proliferation and cell cycle

Unimpeded cell proliferation due to the failure of cell cycle arrest is an important hallmark of cancer. Various tumor suppressor genes are found to be downregulated which causes infinite proliferation of transformed cells with accumulated genetic instability and disruption of cell homeostasis. One of the effective ways to prevent cell proliferation is by targeting the cell cycle checkpoints and myricetin has been confirmed to have a potent therapeutic effect in treating tumor proliferation and progression in many human cancers.

In oesophageal cancer EC9706 cell line, myricetin and 5-FU treatment in combination have reduced the expression of Cyclin D1 and increased p53 compared to the control, therefore, this indicates myricetin with 5-FU causes the cell cycle arrest in G0/G1 phase and prevents its entry into the S-phase, therefore, inhibiting the proliferation of oesophageal cancer cell (Wang et al. 2014; Iyer et al. 2015). Similarly, in T24 bladder cancer cells, it induces cell cycle arrest both in time- and dose-dependent manner at G2/M, by downregulating cyclin B1, cdc 2, and by phosphorylating and activating p38 MAPK pathway leading to G2/M cell cycle arrest and apoptosis (Sun et al. 2012). Likewise, myricetin treated MCF-7 cells revealed decreased expression of Cyclin D1, PCNA, survivin, and β-catenin, therefore, it is established that myricetin reduces cell viability, causes cell cycle arrest via Wnt pathway. The possible underlying mechanism is that myricetin-treated MCF-7 cells display loss of Wnt compared to the untreated cells. Therefore, cell cytoplasm will have a low level of β-catenin as it gets continuously degraded by axin compounds, e.g. GSK3β, which phosphorylates the amino-terminal of β-catenin, and subsequently gets degraded by ubiquitin. The lower level of β-catenin responsible for the reduced expression of cyclin D1, survivin, and PCNA ultimately causes cell cycle arrest, induces apoptosis, and inhibit the proliferation of cancer cells (Jiao and Zhang 2016; Iyer, Gopal et al. 2015).

Similarly, in skin cancer, which is quite prevalent in the West, Myricetin at 40uM concentration induces cell cycle arrest at sub G0 phase of A431 skin cancer cells in a dose-dependent manner (Sun et al. 2018), whereas in HepG2 cells of hepatocellular carcinoma, myricetin inhibits G2/M transition by two different mechanisms. First, myricetin enhances the phosphorylation of CDK1 protein at Thr14/Tyr15, which in turn causes a conformational change and alteration in the orientation of ATP, thereby hampering CDK1 activity (Devi et al. 2015). Therefore, Myricetin inhibits the formation of Cyclin B/CDK1 complex and leads to cell cycle arrest. Moreover, myricetin also causes cell cycle arrest by reactivating tumor suppressor gene, i.e. p53 and enhancing the expression of CDK inhibitors like p21 and p27. Therefore, myricetin as a flavonoid has immense potential to inhibit the cell cycle progression if the cells are in distressed condition. Kwun et al. have confirmed that 100uM myricetin increases the percentage of human papillary thyroid cancer cells (SNU-790 HPTC Cells) in sub G1 phase as compared to untreated control cells (3.93 ± 0.27% versus 24.57 ± 0.37%, respectively) and thus inhibits the progression of a cell from G1/S phase (Kwun et al. 2017).

Effects of myricetin on immunomodulation

One of the striking features of tumor cells is that they can evade destruction by the immune system by exploiting several mechanisms. Otherwise, the antigen expressed by primary tumor would have been recognized by cytotoxic T-cell with MHC 1 and would be consequently degraded by T-cell. Cancer cells can modulate the expression of various molecules involved in immune destruction mechanism and few immune cells in fact, under certain conditions, can favor tumor growth, invasion, and metastasis. In addition to evading, the immune response tumor cells can also co-opt with the immune system by modulating the tumor stromal cells which includes various cell types like fibroblasts, endothelial cells, nerve cells, immune cells, and the extracellular matrix (ECM) and help in maintaining tissue homeostasis (Nelson et al. 2010; Franco et al. 2011; Janssen et al. 2017; Erkan 2013a). Stromal cells support tumor cell growth by inducing angiogenesis. Another important cell from stroma is macrophage, which under the influence of interleukins (IL-4, IL-6, IL-10), can polarize and develop into M1 or M2 macrophages and are known TAMs (tumor-associated macrophages). M1 is anti-tumor while M2 is the pro-tumor TAMs. Recent studies suggest that various types of TAM populations co-exist and some of which have features of both M1 and M2 TAMs (Xue et al. 2014). The anti-tumor TAMs kill the tumor cell by producing I IL-12, IL-6, CXCL9, and nitric oxide (Yuhui Huang and Matija Snuderl 2018). “M2 TAMs promote tumor growth by inducing angiogenesis through IL-10 and CCL22 and by suppressing immune system by inhibiting NK cells, T cells, and DCs by arginine deprivation through arginase expression, facilitate invasion by remodeling the stroma through matrix metalloproteases, and increase metastatic tumor cell shedding through abnormal tumor vasculature” (Yuhui Huang and Matija Snuderl 2018; Dimitrova et al. 2009), all of which are important factors for metastasis. Direct inhibition of M2 can be a potential target to inhibit metastasis.

Apart from TAMs, other important examples of immunosuppressive cells are CD4+, CD25+ and regulatory T cells (Treg). Treg is responsible for edging the immune response to be displayed only by normal tissues, thus preventing autoimmune diseases; however, this inhibitory function is adopted by tumor cells to evade destruction from the immune system and promote invasion and metastasis.

Tregs are mostly CD4 + T cells that express IL-2 receptor chain-α (CD25) and transcription factor forkhead-box P3 (FOXP3). The immunosuppressive activity of Treg is mediated by TGF- β and IL-10 that reduces cell viability and induces cell-cycle arrest or apoptosis of NK and effector cytotoxic T-cells (CD8 +). This is done through inhibition of IL-2 production, which also inhibits maturation of dendritic cells and can directly inhibit CD8 + T cell-mediated cytolysis through TGF-β dependent inhibition of degranulation. Therefore, the most important markers/players of concomitant immunity are cytotoxic T-cells, Natural Killer cells, and M1-like macrophages actively inhibiting metastases of both early and late metastatic stage, Cytotoxic T-cells and Natural Killer cells are inhibited by Tregs and M2-like macrophages which lead to invasion and metastases. Therapeutics can ultimately prevent metastasis and angiogenesis by: (1) inhibiting immunosuppressive molecules like CSF1, CXCL12, IL-10, IL-2, IL-6, IL-12, TGF-β secreted by the primary tumor, (2) escape from immune destruction or (3) by inhibiting Treg and TAMs. In mice experimental model, myricetin was shown to reduce the secretion of MHC II, TNF-α, IL-6, CD40, and IL-12 by blocking mobile and endocytic capacity of LPS-stimulated DCs. Additionally, myricetin exhibits its immunosuppressive property by downregulating the expression of IL-2 both at transcript and protein level in mouse EL-4T cells. 100 µM myricetin treatment completely blocks the IL-2 transcript expression. Even though a lot of evidence is available to prove its immunomodulatory effects, additional research needs to be conducted to utilize it as an immunomodulatory drug.

Effects of myricetin as an anti-invasive and anti-metastatic agent

Following lung cancer, breast cancer is the 2nd most leading cause of death overall and the most frequent in women. In 2018, 2 million new cases have been diagnosed and are expected to increase worldwide. The poor prognosis of breast cancer and resistance to therapy has been reported to be due to 30% overexpression of MEK. The overexpressed MEK gets autonomous activation without extracellular ligand that leads to a progression of the tumor by blocking apoptosis through TNF (Yi et al. 2015; Jiao and Zhang 2016; Ci et al. 2018). MAPK, ERK pathways facilitate cancer cell proliferation and promote the mobility of pancreatic cells leading to invasion and metastasis of pancreatic cancer cells.

Myricetin halts the proliferation of MCF-7 breast cancer cells by inducing apoptosis via MEK/ERK pathway (Jiao and Zhang 2016). Simultaneously, it reduces the viability of MCF-7 cells by inhibition of the P21-activated protein kinase (PAK 1) pathway which has been reported to have a strong association with the invasion and metastasis of colorectal cancer, hepatocellular carcinoma, and prostate cancer (Iyer et al. 2015; Jaime DeSantiago 2015). Therefore, it is evident that PAK1 plays a significant role in the contribution to tumor growth and development.

Ci et al. (2018) have reported that myricetin can inhibit adhesion, migration, and invasion in human breast cancer brain metastasis cell lines (BCBM, MDA-MB‐ 231Br) in vitro by downregulating the expression of MMP-9, MMP-2, and ST6GALNAC5 (Kim et al. 2018). Likewise, in T24 bladder cancer also myricetin downregulates the expression of MMP-9. MMPs play a crucial role in multiple stages of tumor development like growth, migration, and angiogenesis as they play a significant role in the destruction of extracellular matrix protein and tissue remodeling.

In vivo study on 4T1 mouse lung metastasis model has established that myricetin treatment reduces both the size and number of tumor nodules in mice model in contrast with the vehicle mice and did not show any signs of adverse health or pain, and toxicity compared to the control. Therefore, it has been confirmed that myricetin shows anti-metastatic activity both in vitro and in vivo and it blocks cancer metastasis at a relatively lower concentration i.e., the mice receiving 50 mg/kg of myricetin showed 82% reduction in the tumor metastasis compared to the vehicle. Further, other chemopreventive agents like resveratrol at 200 mg/kg induced an 85% decrease in metastasis in lung cancer, whereas luteolin has shown only 70% decrease in metastasis when given orally at a concentration of 50 mg/kg in colon tumor cells (Lee et al. 2012). In prostate cancer, myricetin inhibits epithelial–mesenchymal transition (EMT) important for cancer progression and metastasis by upregulating E-cadherin and downregulating N-cadherin and Vimentin in compare to control (Yea and Zhanga 2018). Moreover, the anti-metastatic effect of myricetin was demonstrated in vivo in the PC3 subcutaneous xenograft nude mice model as myricetin treatment suppressed the growth of xenograft tumor. Further IHC analysis of the xenograft tumor showed an increased level of cleaved caspase 3 and E-cadherin while N-cadherin and vimentin were reduced in myricetin-treated mice compared to the control. Thus, it is confirmed that myricetin inhibits invasion, metastasis, and EMT in PCa cells. In choriocarcinoma, i.e., JEG-3 and JAR cells, 20 µM myricetin treatment reduces the invasion by 90%, with the VEGFA concentration found to be decreased by 40% along with the downregulation in the expression level of proangiogenic factors like MMP-2, MMP-14, and foxhead box protein M1 (FoxM1), while the expression of anti-angiogenic molecules was upregulated like Flt-1. Myricetin further inhibits angiogenesis by increasing the expression of TIMP2, an inhibitor of MMP2.

Myricetin restores aberrant signaling pathway

Cell signaling enables cells to communicate with each other and their microenvironment by sensing various external cues that drive changes in the gene expression of the key molecules; therefore, the cells respond depending on the purpose of the signaling. These events proceed from membrane to nucleus via a series of protein modifications mediated by specific enzymes such as protein kinases. These subsequently trigger the recruitment and activation of linker or scaffolding proteins like the modification of GTP-coupled intermediates serving as second messengers. They also cause an increase in the concentration of intracellular calcium, and ultimately also lead to the mobilization of transcription factors for gene activation in the nucleus. The identity of specific protein kinases, G-proteins, and accessory intermediates involved in each signaling pathway depends on the specific receptor and cell type involved. In a normal cell, receptor-mediated signal transduction is a fundamental cellular process essential for communicating events between the cell surface and the extracellular environment that consequently leads to a change in gene expression in the nucleus. In cancer cells, this signaling mechanism is overexpressed to a level that the cell loses its control over proliferation, cell cycle, and differentiation. It is quite challenging to control them as they are normal cells undergoing abnormal cell growth. Thus, different conventional treatments to target and kill these cancer cells have various side effects which are irreversible and affect the lifestyle and health of the patients. From the perspective of this effect, researchers found a unique option, i.e., chemoprevention to prevent or to an extent treat the cancer cells without affecting the normal cells. Chemoprevention is now widely used throughout the world including various natural products existing on the planet and used by humans for consumption. A great example in this scenario is curcumin, commonly used as a form of coloring agent or spice to enhance the taste of food. A variety of plants, fruits, and vegetable products are researched and tested to screen for the bioactive compounds for treating cancer and achieved very positive results from most of the products. Here we will discuss the effect of myricetin on signal transduction pathways (Devi et al. 2015).

All signal transduction pathways are critical for a cell to function normally; if one of them goes haywire the whole cell either undergoes apoptosis or proliferates uncontrollably leading to tumor development. Mutation in proteins such as MEK, ERK, H-Ras, Raf, NRAS, and BRAS leads to tumorigenesis or carcinogenesis. The key molecule of the MAP kinase pathway is MEK, whose main role is to perform neoplastic transformation, tumor growth, invasion, and metastasis. Various growth factors including EGF, mutant Ras, UV, etc. are responsible for activating this pathway. Myricetin suppresses the transformation by inhibiting the activation of TPA, EGF, and Ras by downregulating the function of MEK protein, by directly binding to MEK1 at a different binding region from ATP (Kim et al. 2018).

JAK STAT3 pathway is mainly functional for cell growth, immune response, inflammation, differentiation, and apoptosis. The main role in this pathway is played by JAK and STAT’s phosphorylation which ultimately activates the downstream molecules to undergo the cellular functions. Myricetin targets the catalytic binding site of JAK1 protein, thereby preventing phosphorylation of STAT3 and JAK1. It also elevates the phosphorylation of EGFR at Tyr845, 992, 1045, 1068, and 1173 and inhibits the phosphorylation of endogenous EGFR sites (Devi et al. 2015) (Fig. 3). AKT pathway, also known as PI3K pathway, is important for cell survival, cell size control, response to nutrient availability, tissue invasion, and angiogenesis. It regulates Cyclin D1 activity that is required for cell transformation. Myricetin deters AKT function by binding to the AKT–ATP biding site and simultaneously downregulating CyclinD1 and NF-κB protein expression. Additionally, it inhibits PI3 kinase and phosphorylation of AKT and IKBα which in turn leads to the downregulation of NF-κB (Xie and Zheng 2017).

Fig. 3.

Fig. 3

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Myricetin and its diverse effects on molecular markers and signaling pathways: the above figure diagrammatically explains the mechanism of action of myricetin which acts as a potent inhibitor of various signaling molecules, molecular markers, and ligands or immunoproteins to prevent cancer development and progression by interfering in various signaling pathways (for e.g. NF-κB, PI3K, WNT, JNK) that leads to inhibition of various hall marks of cancer including inflammation, immunomodulation, cell proliferation, differentiation, apoptotic induction, angiogenesis, cell invasion, and migration

WNT pathway plays a vital role in cell proliferation, progression, and differentiation. With a weak WNT signal, in the classical WNT pathway, the level of β-catenin drops, and the latter degrades by auxin compounds followed by ubiquitination. WNT pathway is activated upon stimulation of cells then combines with FZD proteins and activates GSK3β through phosphorylation. The phosphorylated GSK3β affects auxin which cannot trigger phosphorylation or ubiquitylation of β-catenin, thereby making it stable (Jiao and Zhang 2016). Additionally, myricetin attenuates the expression of COX2, leading to reduced inflammation, and simultaneously downregulates the expression of CyclinD1, c-myc, MMP7, CD44, Bcl-2, VEGF, and survivin to check cell proliferation, apoptosis induction, angiogenesis, etc.

Myricetin in combination therapy

Paclitaxel (100 nM), a chemotherapeutic, did not show any marked cytotoxicity in A2780 and OVCAR3 cell lines when used alone; however, when used in combination with 5 μM of myricetin, a significant reduction of cell viability was observed and the combination therapy reduced cell viability by 50%. Following the cytotoxic evaluation of myricetin with Paclitaxel in combination, they further investigated the mechanism that myricetin employs to enhance the therapeutic index of paclitaxel and that the myricetin treated cells showed a significant reduction in MDR-1 receptor. MDR-1 is a transmembrane phosphor-glycoprotein, which acts as an ATP exporter and known to be responsible for the reduced build-up of drugs in transformed cells (Chen et al. 2009; Alvarez et al. 1995). Overexpression of MDR-1 has been exhibited by aggressive ovarian cancer cells that are resistant to paclitaxel treatment (Chen et al. 2009). Therefore, it explains well that myricetin enhances the chemotherapeutic index of paclitaxel by reducing the expression of MDR-1. The result suggests that treatment of ovarian cancer patients is potentially effective by monothematic use of myricetin. Myricetin has been reported to have a reduced inhibitory effect on tumor growth in oesophageal cancer EC9706 cell Xenograft mice model in vivo than 5-FU alone. However, a substantial decrease in tumor growth was observed in tumor treated with myricetin in combination with 5-FU. Therefore, the result confirmed that myricetin acts as a powerful chemosensitizer to reduce tumor growth in combination with 5-FU in oesophageal cancer.  Paclitaxel (a microtubule stabilizer) causes cell cycle arrest in G2 and induces DNA lesion when used alone against HT-29 human colon cancer, however, when used in combination, myricetin sensitized the colon cancer cells to the chemo-compound. It has been proved that co-treatment of 100 nM PTX with 32uM myricetin enhances the level of phosphorylated γH2AX compared to PTX treatment alone. Phosphorylated γH2AX is a hallmark of DNA double strand break, therefore, elevated level of phosphorylated γH2AX induces apoptosis. Thus co-treatment of myricetin with PTX shows a synergistic effect. Taken altogether, it was evident of the sensitizing effect of myricetin, probably because of the inhibitory effect on hFEN1. The synergistic action of myricetin and eugenol was studied in combination with cisplatin against the HeLa cell. The combination induced apoptosis by changing the mitochondrial membrane potential and increased caspase-3 activity over the control. The combination also increased the proportion of cells at Go/G1 phase compared to the control (Hassan et al. 2017).

Myricetin and epigenetics

As discussed earlier, cancer results from genetic alteration along with aberrant epigenetic regulation. However, the reversible nature of epigenetics machinery like DNA methylation, histone modification etc. makes it an attractive molecular target for cancer chemoprevention (Busch et al. 2015; Gilbert and Liu 2010). DNA methylation is carried out by DNA methyltransferases (DNMTs) while histone deacetylase (HDAC) removes the acetyl group from histone protein rendering them transcriptionally inactive (Hong et al. 2012). Myricetin acts as a direct inhibitor of human DNMT 1 and HDAC inhibitor in human HepG2 cells. However, the epigenetic modulation by myricetin is in its early infancy and a lot more research needs to be conducted in different types of cancer to reveal its epigenetic modification mechanism.

Encapsulation of myricetin to increase bioavailability and enhance anti-cancer efficacy

As myricetin is sparingly soluble in aqueous solution, it has been dissolved in DMSO in all reported experiments. DMSO concentration above 0.3% had been confirmed to be toxic for the cells, thus, to investigate the anticancer effect of myricetin, the DMSO concentration should either be 0.3% or lesser. In various in vitro studies, myricetin was used between 5 and 100 μM concentration, while for the in vivo experiments, 5–50 mg/kg body weight were tested to investigate its anticancer efficacy which will exceed the DMSO concentration beyond 0.3%. Low bioavailability, aqueous insolubility, and the thermolabile nature of myricetin pose a challenge for using it as chemotherapy (Semwal et al. 2016). Therefore, clinical use of myricetin would be limited due to its pharmacodynamic properties. Researchers have employed a variety of strategies to increase the solubility and consequent bioavailability of this compound. One such successful strategy used so far is forming a conjugate of hydroxylated—β-cyclodextrin (a modified form of β-CD) with myricetin. The application of HP-β-CD/myricetin conjugate in rats enhanced oral bioavailability of myricetin by 9.4 folds in comparison to free myricetin besides improving its antioxidant activity (Yao et al. 2014). Further, in human glioblastoma cells (DBTRG cells), encapsulated myricetin with nanosized Pluronic P123/F68 mixed micelles boosted the cytotoxic profile of myricetin. The encapsulated form, i.e., myricetin-loaded mixed micelles (MYR-MCs) induced apoptosis via the mitochondrial-dependent pathway by targeting EGFR and PI3k/AKT pathway. The miR-21 expression was inhibited by MYR-MCs in a concentration-dependent manner which in turn downregulates the expression of EGFR, p-Akt, and K-ras to induces apoptosis (Wang et al. 2016). Even though HP-β-CD/myricetin inclusion and MYR-MCs encapsulation are the alternate modes of delivery for myricetin, still more research is required for better delivery and detailed evaluation of its pharmacokinetics to potentiate its therapeutic efficacy.

Conclusion and future perspective

Plant polyphenols have earned a lot of consideration in the last few decades as potential anti-cancer agents with differential response and a safer profile over chemotherapeutics. Myricetin, a polyphenol with a repertoire of pharmacological activities, has shown significant effects as an anti-inflammatory, anti-cancer, and anti-diabetes agent, and against neurodegenerative disorders. Due to the pleiotropic nature of cancer and its variability, they pose the challenge of targeting a particular molecule or the signaling pathway, however, myricetin has the potential to target multiple events to encumber tumor progression, induce cell death, prevents metastasis etc. as established from in vitro studies. With the ongoing research on myricetin, new mechanistic and target molecules are rising that will take chemoprevention to the next level in cancer treatment. But still there are limited number of studies available for validation of its in vitro effects on in vivo model. Myricetin had been found to be effective and has shown synergism with various other polyphenols as well as chemotherapeutics when used in combination. However, more combinatorial studies need to be explored to evaluate their chemotherapeutic index. The poor bioavailability and aqueous solubility limit the application of myricetin as an anti-cancer agent, as well as toxicity profile of myricetin needs to be explored against normal cells. Even though there are alternate routes to increase its delivery and enhance its bioavailability, i.e., HP-β-CD/myricetin inclusion and encapsulated form, more strategies need to be developed to optimize the delivery and evaluate the pharmacokinetics to improve its therapeutics potential.

Author contributions

NA: formulation and writing the manuscript, AH and SP: editing the manuscript, MW and KV: collected various research articles for this review.

Compliance with ethical standards

Conflict of interest

No conflict of interest of the authors is involved with the publication.

Ethical statement

This paper is not been considered in this or any other form for publication elsewhere. No ethics have been violated in compiling this article.

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